L-Glutamate is one of the most abundant excitatory neurotransmitters in the mammalian brain and, as such, is responsible for the majority of synaptic transmission in the central nervous system. Despite the fact that this acidic amino acid is known to interact with binding sites on a number of different proteins (excitatory neurotransmitter receptors, transport systems, and enzymes) during the process of neurotransmission, specific structural details of these interactions are lacking.
Considerable evidence has firmly established the existence of several classes of postsynaptic receptors through which the excitatory action of L-glutamate is mediated, as well as the presence of a high affinity transport system that terminates the resultant excitatory signal. In vivo, endogenous L-glutamate or a glutamate-like molecule binds to each of these sites, while in vitro, various glutamate analogues exhibit selective affinities and thus can pharmacologically differentiate among individual receptor classes. Specifically, three major types of excitatory amino acid transmitter receptors have been distinguished by their characteristic interactions with various agonists: N-methyl-D-aspartate (NMDA), kainate (KA), and quisqualate (QA). Despite the fact that these analogues have been invaluable in identifying and characterizing the various classes of transmitter receptors empirically, a unified model to explain the observed binding specificities in terms of specific molecular conformations has been elusive.
Unlike systems that depend upon rapid chemical degradation for transmitter signal termination, L-glutamate is removed from the synaptic cleft by high affinity transport. Again, little is known about the conformational requirements of substrate binding to this transport system, although several competitive inhibitors have been identified. Interest in the functional characteristics of this uptake mechanism has dramatically increased with the recent finding that excessive levels of glutamate (as well as other excitatory agonists) are neurotoxic and appear to play a significant role in neurological disorders such as ischemia, hypoglycemia, epilepsy, Huntington's disease and Alzheimer's disease.
Thus, the discovery of additional compounds which affect the transport system are critical to understanding the transport system and would be useful as therapeutics for treatment of the various disorders associated with the transport system. Applicants have satisfied this need with the discovery of compounds which are potent and selective inhibitors of the high affinity transport of L-glutamate.